As is known, (all-rac)-α-tocopherol (or as it has mostly been denoted in the prior art, “d,l-α-tocopherol”) is a mixture of four diastereomeric pairs of enantiomers of 2,5,7,8-tetra-methyl-2-(4′,8′,12′-trimethyl-tridecyl)-6-chromanol (α-tocopherol), which is the biologically most active and industrially most important member of the vitamin E group.
Many processes for the manufacture of “d,l-α-tocopherol” (referred to as such in the literature reviewed hereinafter) by the reaction of 2,3,5-trimethyl-hydro-p-benzoquinone (TMHQ) with isophytol or phytol in the presence of a catalyst or catalyst system and in a solvent or solvent system are described in literature.
One raw material for the production of 2,3,6-trimethylphenol (“2,3,6-TMP”, starting material for TMHQ) is m-cresol. Due to limited availability and an increasing demand for m-cresol, prices for m-cresol and 2,3,6-TMP are growing. Therefore a m-cresol-independent access to TMHQ is strongly desired.
One option for a m-cresol free access to TMHQ could be a reaction sequence starting from 2,6-dimethyl-p-benzoquinone (“2,6-DMQ”).
The hydrogenation of 2,6-DMQ to 2,6-dimethyl-hydro-p-benzoquinone (“2,6-DMHQ”) is a literature-known reaction. There are procedures, using stoichiometric reducing agents such as sodium dithionite [Na2(S2O4)] in different solvents (see Carpino, Louis A.; Triolo, Salvatore A.; Berglund, Richard A.; J. Org. Chem. 1989, 54(14), 3303-3310; He, Li; Zhu, Chenjiang; He, Xiaopeng; Tang, Yanhui; Chen, Guorong; Zhongguo Yiyao Gongye Zazhi 2006, 37(5), 301-302; and CN 1 699 356 A).
Modern syntheses describe catalytic hydrogenations using hydrogen in presence of a heterogeneous catalyst [e.g. Pd-catalyst, methanol, room temperature] as claimed in AU 2004 201 149 A1.
The closest state of the art for a reaction sequence from DMQ to TMHQ (see FIG. 1) is disclosed in JP 2006-249 036.
In this reaction sequence each of the three reaction steps is carried out in a different solvent: For the hydrogenation of 2,6-DMQ to 2,6-DMHQ alcohols (iso-propanol), alkyl esters (butyl acetate) or ethers (diethyl ether) are claimed as solvents. The aminomethylation of 2,6-DMHQ is carried out in aromatic hydrocarbons, such as toluene, benzene, ethylbenzene or xylene. And the final de-amination is described in lower aliphatic alcohols (methanol, iso-propanol), alkyl esters (butyl acetate) or ethers (tetrahydrofuran, dioxane). This procedure requires not only the use of various solvents but also the technical operations for two to three solvent changes (distillation).
To by-pass the disadvantage of solvent changes and to achieve high selectivity and yield, it was investigated to carry out as many steps as possible of the reaction sequence from 2,6-DMQ to TMHQ in the same solvent. It was further investigated to find solvents especially suitable for such reaction steps. MTBE (methyl tert.-butyl ether), methoxycyclopentane, ethyl tert.-butyl ether (ETBE) and tert.-amyl methyl ether were found as being especially suitable for the purpose of the present invention. MTBE, ETBE and methoxycyclopentane have the further advantage from an economical point of view that they are cheap. ETBE e.g. is used as antiknock agent for biodiesel. MTBE has the further advantage that it would simplify the work-up because it does not form peroxides.
Disadvantages of the processes known from the prior art are also that larger amounts of bis-Mannich adducts such as e.g. 3,5-dimethyl-2,6-bismorpholinomethyl-hydro-p-benzoquinone are formed as by-products. These by-products have to be removed before TMHQ can be further reacted with isophytol and/or phytol and/or derivatives of isophytol or phytol to vitamin E, because the further reaction products are much more difficult to remove than the bis-Mannich adducts themselves. Advantageously these bis-Mannich adducts are formed in a much lower amount when using the solvents according to the present invention.
Thus, the present invention is directed to a process for the manufacture of 2,3,5-tri-methyl-hydro-p-benzoquinone comprising the following steps:                a) hydrogenating 2,6-dimethyl-p-benzoquinone with hydrogen in the presence of a hydrogenation catalyst in an organic solvent to obtain 2,6-dimethyl-hydro-p-benzoquinone;        b) reacting 2,6-dimethyl-hydro-p-benzoquinone with a secondary amine and formaldehyde in an organic solvent to obtain 2,6-dimethyl-3-(N,N-disubstituted aminomethyl)-hydro-p-benzoquinone;        c) reacting 2,6-dimethyl-3-(N,N-disubstituted aminomethyl)-hydro-p-benzoquinone with hydrogen in the presence of a hydrogenolysis catalyst in an organic solvent to obtain 2,3,5-trimethyl-hydro-p-benzoquinone;        wherein the organic solvent in all steps a), b) and c) is independently selected from the group consisting of methyl tert.-butyl ether, ethyl tert.-butyl ether, methyl tert.-amyl ether, methoxycyclopentane and any mixtures thereof.        
Preferably the organic solvent in all steps a), b) and c) is the same. More preferably this organic solvent is methyl tert.-butyl ether.
Since the obtained 2,3,5-trimethyl-hydro-p-benzoquinone can be further reacted with isophytol and/or phytol and/or derivatives of isophytol or phytol vitamin E, the present invention is also directed to
a process for the manufacture of vitamin E comprising at least one of the steps a) to c) according to the process of the present invention to obtain 2,3,5-trimethyl-hydro-p-benzoquinone which is further reacted with isophytol and/or phytol and/or derivatives of isophytol or phytol vitamin E according to processes known to the person skilled in the art.
Since 2,3,5-trimethyl-hydro-p-benzoquinone may first be converted to 2,3,5-trimethyl-hydro-p-benzoquinone acetate before this 2,3,5-trimethyl-hydro-p-benzoquinone acetate is reacted with isophytol and/or phytol and/or derivatives of isophytol or phytol to vitamin E acetate according to processes known to the person skilled in the art, the present invention is furthermore also directed to
a process for the manufacture of vitamin E acetate comprising at least one of the steps a) to c) according to the process of the present invention to obtain 2,3,5-trimethyl-hydro-p-benzoquinone, which is then converted to 2,3,5-trimethyl-hydro-p-benzoquinone acetate, which is further reacted with isophytol and/or phytol and/or derivatives of isophytol or phytol to vitamin E.
Since the single steps have not been described using these solvents before, the present invention is also directed to                a process for the manufacture of 2,6-dimethyl-hydro-p-benzoquinone comprising the step of hydrogenating 2,6-dimethyl-p-benzoquinone with hydrogen in the presence of a hydrogenation catalyst in an organic solvent, wherein the organic solvent is selected from the group consisting of methyl tert.-butyl ether, ethyl tert.-butyl ether, methyl tert.-amyl ether, methoxycyclopentane and any mixtures thereof;        a process for the manufacture of 2,6-dimethyl-3-(N,N-disubstituted aminomethyl)-hydro-p-benzoquinone (preferably of 2,6-dimethyl-3-morpholinomethyl-hydro-p-benzoquinone) comprising the step of reacting 2,6-dimethyl-hydro-p-benzoquinone with a secondary amine (preferably with morpholine) and formaldehyde in an organic solvent to obtain 2,6-dimethyl-3-(N,N-disubstituted aminomethyl)-hydro-p-benzoquinone (preferably 2,6-dimethyl-3-morpholinomethyl-hydro-p-benzoquinone), wherein the organic solvent is selected from the group consisting of methyl tert.-butyl ether, ethyl tert.-butyl ether, methyl tert.-amyl ether, methoxycyclopentane and any mixtures thereof;        a process for the manufacture of 2,3,5-trimethyl-hydro-p-benzoquinone comprising the step of reacting 2,6-dimethyl-3-(N,N-disubstituted aminomethyl)-hydro-p-benzoquinone (preferably 2,6-dimethyl-3-morpholinomethyl-hydro-p-benzoquinone) with hydrogen in the presence of a hydrogenolysis catalyst in an organic solvent to obtain 2,3,5-trimethyl-hydro-p-benzoquinone, wherein the organic solvent is selected from the group consisting of methyl tert.-butyl ether, ethyl tert.-butyl ether, methyl tert.-amyl ether, methoxycyclopentane and any mixtures thereof;as well as to processes, where two of the three steps are carried out in these solvents, i.e. to        a process for the manufacture of 2,6-dimethyl-3-(N,N-disubstituted aminomethyl)-hydro-p-benzoquinone (preferably 2,6-dimethyl-3-morpholinomethyl-hydro-p-benzoquinone) comprising the following steps:                    hydrogenating 2,6-dimethyl-p-benzoquinone with hydrogen in the presence of a hydrogenation catalyst in an organic solvent to obtain 2,6-dimethyl-hydro-p-benzoquinone;            reacting 2,6-dimethyl-hydro-p-benzoquinone with a secondary amine (preferably with morpholine) and formaldehyde in an organic solvent to obtain 2,6-dimethyl-3-(N,N-disubstituted aminomethyl)-hydro-p-benzoquinone (preferably 2,6-dimethyl-3-morpholinomethyl-hydro-p-benzoquinone);            wherein the organic solvent is independently selected from the group consisting of methyl tert.-butyl ether, ethyl tert.-butyl ether, methyl tert.-amyl ether, methoxycyclopentane and any mixtures thereof;                        a process for the manufacture of 2,3,5-trimethyl-hydro-p-benzoquinone comprising the following steps:                    i) reacting 2,6-dimethyl-hydro-p-benzoquinone with a secondary amine (preferably with morpholine) and formaldehyde in an organic solvent to obtain 2,6-dimethyl-3-(N,N-disubstituted aminomethyl)-hydro-p-benzoquinone (preferably 2,6-dimethyl-3-morpholinomethyl-hydro-p-benzoquinone);            ii) reacting 2,6-dimethyl-3-(N,N-disubstituted aminomethyl)-hydro-p-benzoquinone (preferably 2,6-dimethyl-3-morpholinomethyl-hydro-p-benzoquinone) with hydrogen in the presence of a hydrogenolysis catalyst in an organic solvent to obtain 2,3,5-trimethyl-hydro-p-benzoquinone,            wherein the organic solvent used in steps i) and ii) is independently selected from the group consisting of methyl tert.-butyl ether, ethyl tert.-butyl ether, methyl tert.-amyl ether, methoxycyclopentane and any mixtures thereof;                        a process for the manufacture of 2,3,5-trimethyl-hydro-p-benzoquinone comprising the following steps:                    a) hydrogenating 2,6-dimethyl-p-benzoquinone with hydrogen in the presence of a hydrogenation catalyst in an organic solvent to obtain 2,6-dimethyl-hydro-p-benzoquinone;            b) reacting 2,6-dimethyl-hydro-p-benzoquinone with a secondary amine (preferably with morpholine) and formaldehyde in an organic solvent to obtain 2,6-dimethyl-3-(N,N-disubstituted aminomethyl)-hydro-p-benzoquinone (preferably 2,6-dimethyl-3-morpholinomethyl-hydro-p-benzoquinone);            c) reacting 2,6-dimethyl-3-(N,N-disubstituted aminomethyl)-hydro-p-benzoquinone (preferably 2,6-dimethyl-3-morpholinomethyl-hydro-p-benzoquinone) with hydrogen in the presence of a hydrogenolysis catalyst in an organic solvent to obtain 2,3,5-trimethyl-hydro-p-benzoquinone;            wherein the organic solvent in steps a) and c) is independently selected from the group consisting of methyl tert.-butyl ether, ethyl tert.-butyl ether, methyl tert.-amyl ether, methoxycyclopentane and any mixtures thereof.                        
Also here preferably the organic solvent is the same in two steps. More preferably this organic solvent is methyl tert.-butyl ether.